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Tumor Biology |
Departamento de Biología Molecular, Centro de Biología Molecular "Severo Ochoa," Universidad Autónoma de Madrid-Consejo Superior Investigaciones Científicas, Universidad Autónoma de Madrid, 28049 Madrid, Spain [J. M. C., M. L. d. H., G. S., M. C.]; Department of Pathology, College of Medicine, Yonsei University, Seoul, Korea [H. K.]; and The Burnham Institute, La Jolla, California 92037 [J. M. C., M. K., S. K., J. M. Z., H. M., J. C. R.]
Mitochondrial H+-ATP synthase is required for cellular energy provision and for efficient execution of apoptosis. Almost one century ago, Otto Warburg proposed the hypothesis that mitochondrial function might be impaired in cancer cells. However, his hypothesis was never demonstrated in human carcinomas. In this study, we have analyzed the expression of the ß-catalytic subunit of the H+-ATP synthase (ß-F1-ATPase) of mitochondria in carcinomas of the human liver, kidney, and colon. We show that carcinogenesis in the liver involves a depletion of the cellular mitochondrial content, as revealed by reduced content of mitochondrial markers, whereas in kidney and colon carcinomas, it involves a selective repression of the expression of the ß-F1-ATPase concurrent with an increase in the expression of the glycolytic glyceraldehyde-3-phosphate dehydrogenase. Both mechanisms limit mitochondrial cellular activity in cancer, strongly supporting Warburg’s hypothesis, and suggest a mechanism for the resistance and compromised apoptotic potential of tumor cells. Furthermore, we show that the metabolic state of the cell, as defined by a bioenergetic mitochondrial index relative to the cellular glycolytic potential, provides a signature of carcinogenesis of prognostic value in assessing the progression of colorectal carcinomas.
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